Myofibroblast induces hepatocyte-to-ductal metaplasia via laminin–ɑvβ6 integrin in liver fibrosis

Abstract

Hepatocytes undergo the metaplasia into ductal biliary epithelial cells (BECs) in response to chronic injury, and subsequently contribute to liver regeneration. The mechanism underlying hepatocyte-to-ductal metaplasia has not been explored until now. In mouse models of liver fibrosis, a florid BEC response was observed in fibrotic liver, and the depletion of myofibroblasts attenuated BEC expansion remarkably. Then, in hepatocyte fate-tracing mouse model, we demonstrated the conversion of mature hepatocytes into ductal BECs in fibrotic liver, and the depletion of myofibroblasts diminished the hepatocyte-to-ductal metaplasia. Finally, the mechanism underlying the metaplasia was investigated. Myofibroblasts secreted laminin-rich extracellular matrix, and then laminin induced hepatocyte-to-ductal metaplasia through ɑvβ6 integrin. Therefore, our results demonstrated myofibroblasts induce the conversion of mature hepatocytes into ductal BECs through laminin-ɑvβ6 integrin, which reveals that the strategy improve regeneration in fibrotic liver through the modification of specific microenvironment.

Epithelial Plasticity during Liver Injury and Regeneration

“…YAP activation in hepatocytes is required for hepatocyte to biliary transition after DDC-induced liver injury (Pepe-Mooney et al, 2019). In the setting of hepatocellular injury, myofibroblast deletion during CCl 4 , TAA or diethylnitrosamine (DEN) injury models resulted in approximately 50% less hepatocyte to biliary conversion (Xu et al, 2020).…”

A Dynamic Transcriptome Map of Different Tissue Microenvironment Cells Identified During Gastric Cancer Development Using Single-Cell RNA Sequencing

“…FibC4 was characterized by the high expression of IGFBP3 which promoted both fibroblasts into myofibroblasts, and also matrix remodeling ( 57 ). Xu et al showed that myofibroblasts metabolized proteoglycans containing laminin and induced hepatocyte-to-ductal metaplasia based on αvβ6 integrin-induced ( 58 ). Thus, we propose that inhibiting IGFBP3 expression and reducing myofibroblast transformation may be key to preventing IM.…”

Role of Immune Cells in Biliary Repair

“…, and can recruit and activate various immune cells such as T cells, macrophages, and neutrophils to the periductular niche ( 87 – 94 ). These immune cells in turn modify biliary repair by adjusting the proliferating capability of adjacent cholangiocytes ( 95 ), expansion and differentiation of LPC ( 31 , 42 – 44 , 96 ), or plasticity of hepatocytes ( 61 ), etc. Thus, the crosstalk between cholangiocytes and immune cells and the specific role of different immune cell subsets in biliary repair are summarized.…”

“…Myofibroblast-secreted Jagged1 could promote LPC differentiation toward the biliary lineage in the condition of biliary injury ( 31 , 41 , 128 ). Moreover, myofibroblasts can also regulate HCT by interacting with laminin and ITGB6 ( 61 ). Except for the abovementioned functions, HSCs were even reported to gain progenitor features and function as bipotent LPCs to repopulate the liver parenchyma after partial hepatectomy (PHx) ( 129 , 130 ).…”